Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma.
Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma.
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DOI：
10.1038/labinvest.2015.86
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发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Meltzer SJ
中科院分区：
文献类型：
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作者：
Tang X;Wang Y;Fan Z;Ji G;Wang M;Lin J;Huang S;Meltzer SJ
Klotho是一种抗衰老基因，最近被证明有助于人类肝脏肿瘤的发生。此外，已知Wnt信号传导被蛋白klotho拮抗。由于增强的Wnt信号传导在人肝细胞癌（HCC）的肿瘤发生中具有重要作用，我们研究了klotho表达和活性与这种恶性肿瘤中Wnt通路的关系。组织芯片的免疫组化分析显示，klotho表达水平显着低于在癌旁组织，而klotho染色与临床分期和组织学分级呈负相关。klotho表达肿瘤的患者比klotho阴性肿瘤的患者生存期更长。klotho的过表达以及可溶性klotho蛋白的治疗在体外和体内减少肝癌细胞的生长，而klotho沉默增强细胞增殖。此外，klotho的强制表达抑制Wnt/β-连环蛋白信号传导，如通过降低β-连环蛋白的表达、抑制β-连环蛋白从细胞质易位到细胞核以及降低Wnt/β-连环蛋白途径的两个已知靶基因c-myc和细胞周期蛋白D1的表达所证实的。相反，当klotho被抑制性RNA沉默时，Wnt/β-连环蛋白途径的激活增强。此外，研究了恶性肿瘤患者血清中可溶性klotho的水平，结果表明HCC患者的这些水平显著增加。这些数据表明，klotho在HCC中作为肿瘤抑制剂和Wnt/β-连环蛋白途径的抑制剂，并且可溶性klotho是HCC的潜在血清生物标志物。
Klotho, an anti-aging gene, has recently been shown to contribute to human hepatic tumorigenesis. In addition, it is known that Wnt signaling is antagonized by the protein klotho. Because augmented Wnt signaling has an important role in tumorigenesis of human hepatocellular carcinoma (HCC), we studied the relationship of klotho expression and activity to the Wnt pathway in this malignancy. Immunohistochemical analysis performed on tissue arrays revealed that klotho expression levels were significantly lower in HCC than in adjacent noncancerous tissues, while klotho staining was inversely correlated with clinical stage and histologic grade. Patients with klotho-expressing tumors had longer survival periods than did those with klotho-negative tumors. Overexpression of klotho as well as treatment with soluble klotho protein reduced hepatoma cell growth in vitro and in vivo, whereas klotho silencing enhanced cellular proliferation. Moreover, forced expression of klotho inhibited Wnt/β-catenin signaling, as confirmed by reduced expression of β-catenin, inhibition of translocation of β-catenin from the cytoplasm to the nucleus, and reduced expression of c-myc and cyclin D1, two known target genes of the Wnt/β-catenin pathway. In contrast, activation of the Wnt/β-catenin pathway was enhanced when klotho was silenced by inhibitory RNAs. Furthermore, serum levels of soluble klotho in patients with malignant tumors were studied, and results suggested a significant increase in these levels in HCC patients. These data suggest that klotho acts as a tumor suppressor and an inhibitor of the Wnt/β-catenin pathway in HCC, and moreover, that soluble klotho is a potential serum biomarker for HCC.